Process for sizing prednisolone acetate using a supercritical fluid anti-solvent

Abstract

A process employing a supercritical fluid anti-solvent for sizing prednisolone acetate is disclosed. The process optionally incorporates sterilization filters. Average particle sizes of about 1 mu m or less (number average) and narrow particle size ranges are obtainable. The process comprises the steps of (a) forming a solution by dissolving prednisolone acetate in acetone such that the concentration of prednisolone acetate is approximately 80% or less of its solubility in acetone; and (b) transporting the solution formed in step (a) through an orifice having a diameter of 50-100 mu m into a mixer/expander containing compressed CO2, wherein the compressed CO2 is at a temperature from about 40 DEG to 80 DEG C. and has a density less than the density of the solution by at least 0.3 g/cc, to expand the solution so that the acetone dissolves in the CO2 and the prednisolone acetate precipitates.

We claim: 
     
       1. A process for sizing prednisolone acetate which produces a number average particle size of 1 μm or less, a particle see distribution having no particles greater than 10 μm (based on number distribution), and a particle size distribution index of less than 4, wherein the process comprises the steps of: (a) forming a solution by dissolving prednisolone acetate in acetone so that the concentration of prednisolone acetate in the solution is approximately 80% or less of its solubility in acetone; and   (b) transporting the solution formed in step (a) through an orifice having a diameter of 50-100 μm into a mixer/expander containing compressed CO 2 , wherein the compressed CO 2  is at a temperature from about 40° to 80° C. and has a density less than the density of the solution by at least 0.3 g/cc, wherein the solution is expanded so that the acetone dissolves in the CO 2  and the prednisolone acetate precipitates.   
     
     
       2. The process of claim 1 wherein the process produces prednisolone acetate having a number average particle size of 0.5 μm or less and a particle size distribution having no particles greater than 5 μm (based on number distribution). 
     
     
       3. The process of claim 1 wherein the prednisolone acetate concentration in the solution formed in step (a) is from about 0.5 to 0.6% (w/v). 
     
     
       4. The process of claim 3 wherein the prednisolone acetate concentration in the solution formed in step (a) is from about 0.52 to 0.55% (w/v). 
     
     
       5. The process of claim 1 wherein the temperature of the compressed CO 2  is from about 45° to 65° C. 
     
     
       6. The process of claim 1 wherein the temperature of the compressed CO 2  is about 60° C. 
     
     
       7. The process of claim 1 wherein the compressed CO 2  has a density from about 0.30 to 0.41 g/cc. 
     
     
       8. The process of claim 1 wherein the solution enters the orifice at a flow rate from about 2 to 4 ml/min. and the compressed CO 2  enters the mixer/expander at a flow rate from about 50 to 80 standard liters/min. 
     
     
       9. The process of claim 8 wherein the solution enters the orifice at a flow rate from about 2.5 to 3.0 ml/min. and the compressed CO 2  enters the mixer/expander at a flow rate of about 60 standard liters/min. 
     
     
       10. A process for sterilizing and sizing prednisolone acetate which produces a number average particle size of 1 μm or less, a particle size distribution having no particles greater than 10 μm (based on number distribution), and a particle size distribution index of less than 4, wherein the process comprises the steps of: (a) forming a solution by dissolving prednisolone acetate in acetone so that the concentration of prednisolone acetate in the solution is approximately 80% or less of its solubility in acetone;   (b) sterilizing the solution formed in step (a) by transporting it through a sterilizing filter to remove bacteria and other impurities; and   (c) transporting the sterilized solution formed in step (b) through an orifice having a diameter of 50-100 μm into a mixer/expander containing sterile compressed CO 2 , wherein the compressed CO 2  is at a temperature from about 40° to 80° C. and has a density less than the density of the solution by at least 0.3 g/cc, wherein the solution is expanded so that the acetone dissolves in the CO 2  and the prednisolone acetate precipitates.   
     
     
       11. The process of claim 10 wherein the process produces prednisolone acetate having number average particle size of 0.5 μm or less and a particle size distribution having no particles greater than 5 μm (based on number distribution). 
     
     
       12. The process of claim 10 wherein the prednisolone acetate concentration in the solution formed in step (a) is from about 0.5 to 0.6% (w/v). 
     
     
       13. The process of claim 12 wherein the prednisolone acetate concentration in the solution formed in step (a) is from about 0.52 to 0.55% (w/v). 
     
     
       14. The process of claim 10 wherein the temperature of the compressed CO 2  is from about 45° to 65° C. 
     
     
       15. The process of claim 10 wherein the temperature of the compressed CO 2  is about 60° C. 
     
     
       16. The process of claim 1 wherein the compressed CO 2  has a density from about 0.30 to 0.41 g/cc. 
     
     
       17. The process of claim 1 wherein the solution enters the orifice at a flow rate from about 2 to 4 ml/min. and the compressed CO 2  enters the mixer/expander at a flow rate from about 50 to 80 standard liters/min. 
     
     
       18. The process of claim 17 wherein the solution enters the orifice at a flow rate from about 2.5 to 3.0 ml/min. and the compressed CO 2  enters the mixer/expander at a flow rate of about 60 standard liters/min.